肿瘤转移抑制因子CD82/CD9和c-Met介导的信号跨膜转导在肿瘤淋巴转移中作用的研究
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摘要
目的:肝细胞生长因子(hepatocyte growth factor, HGF)是由间质细胞(如成纤维细胞、巨噬细胞)产生的多肽类细胞因子,又称间充质因子。HGF具有许多重要的生物学功能,如促进细胞的增殖、分裂;抑制细胞间隙连接的生成和细胞之间的粘附,导致细胞的离散;上调尿激酶型纤溶酶原激活物及受体(uPA/uPAR)的表达,促进细胞外基质降解;增加细胞骨架蛋白磷酸化,破坏细胞骨架,从而使细胞易于变形和迁移。因此,HGF又称促有丝分裂因子、离散因子、细胞形态发生素或促迁移因子。HGF在胚胎的发育、器官的形成、细胞的生长和迁移过程中发挥重要的调控作用,也与肿瘤的发生、进展、浸润、扩散和转移有着非常密切的关系。
HGF的受体(hepatocyte growth factor receptor, HGFR)是原癌基因c-met编码的产物,又称c-Met。c-Met属于受体酪氨酸蛋白激酶家族成员,常由上皮细胞(如肝、肾、消化道细胞)表达。c-Met在肿瘤细胞表达增加,并与肿瘤细胞转移能力呈正相关。HGF由间质细胞分泌后,经旁分泌途径作用于周围靶细胞。HGF与受体c-Met结合后,导致受体二聚化和活化,进而激活细胞内不同的信号转导途径。已知HGF/c-Met活化的细胞内信号转导途经起码有三条,包括有丝分裂原激活的蛋白激酶信号转导通路(MAPK信号通路)、磷脂酶Cγ1/二脂酰甘油/蛋白激酶C信号转导通路(PLCγ1 /DAG/PKC信号通路)和三磷脂酰肌醇激酶/蛋白激酶B信号转导通路(PI3K/ PKB信号通路)。其中,PI3K/PKB和PLCγ/PKC信号转导途径是调控肿瘤细胞侵袭和转移的重要途径。
KAI-1/CD82和MRP-1/CD9均属于4跨膜蛋白基因家族编码的产物。CD82是肿瘤转移抑制基因KAI-1编码的产物,目前被认为是广谱的肿瘤转移抑制因子。CD9又称细胞运动相关蛋白-1(motility-related protein-1)。二者均可下调癌细胞的运动性,从而抑制肿瘤细胞的浸润转移。对其作用机制研究表明,CD82和CD9通过与c-Met相互作用,抑制HGF诱导的c-Met酪氨酸蛋白激酶的活化,或抑制c-Met与整合素(integrins)的相互作用,下调c-Met对PI3K/PKB和PLCγ/PKC信号转导途径的活化,从而发挥其转移抑制作用。
Hca-F细胞株和HCa-P细胞株为同一来源但具有不同淋巴结转移能力的两个细胞株。Hca-F为高淋巴道转移株,淋巴结转移率为80%,Hca-P为低淋巴道转移株,淋巴结转移率为0-20%。两细胞株淋巴道转移能力差别产生的分子机制尚不十分清楚。本课题主要比较两细胞株CD82/CD9和c-Met的表达以及PI3K/PKB和PLCγ1 /PKC信号转导通路的活性变化,以探讨肿瘤细胞淋巴道转移的分子机制。
方法:小鼠腹水型肝癌Hca-F和Hca-P细胞株于小鼠腹腔培养。分别收集细胞后,分离提取细胞总蛋白,制备胞浆蛋白和颗粒结合蛋白。采用SDS-PAGE、Western Blotting技术及计算机扫描定量分析两细胞株CD82/CD9的表达和PI3K/PKB和PLCγ1 /PKC信号通路的活性。
结果:1)CD82/CD9的表达:CD82在高淋巴道转移株Hca-F细胞和低淋巴道转移株Hca-P细胞中的表达没有显著性差别,Hca-P细胞CD9表达显著高于Hca-F细胞(Hca-P是Hca-F的1.31倍,P=0.4%,n=3),提示CD9可能是影响两细胞株淋巴道转移能力的主要因素。2)PI3K/PKB信号转导通路:采用Western Blotting技术对两细胞株PDK的表达和在细胞中的分布以及PKB磷酸化活化进行了比较分析。结果显示,两细胞株磷酸化PKB的表达无显著性差别;PDK在两细胞株的分布也无显著差异;说明PI3K/PKB信号转导通路不是影响两细胞株淋巴道转移能力主要途径。3)PLCγ1/PKC信号转导通路:采用Western Blotting技术对两细胞株PLCγ1及不同亚型PKCs的活性进行了比较分析。结果显示,淋巴道低转移株Hca-P细胞磷酸化的PLCγ1表达明显低于淋巴道高转移株Hca-F细胞(Hca-P是Hca-F的45.23%倍,P<0.05,n=3);Hca-P细胞中膜结合的PKCα、PKCβ1和PKCβ2含量明显低于Hca-F细胞(Hca-P细胞PKCα、PKCβ1和PKCβ2分别是Hca-F细胞的71.75%、76.80%和73.16%,P<0.05,n=3)。说明高转移株Hca-F细胞的PLCγ1/PKC信号转导通路的活性高于低转移株Hca-P细胞。PLCγ1/PKC信号转导通路可能是影响两细胞株淋巴道转移能力主要信号途径。
结论:肿瘤转移抑制因子CD9在淋巴道低转移Hca-P细胞高表达;淋巴道低转移Hca-P细胞中的PLCγ1/PKC信号转导通路活性低。这可能是Hca-P细胞具有较低淋巴结转移能力的因素之一。推测可能是高表达的CD9与c-Met相互作用,抑制c-Met对Hca-P细胞PLCγ1/PKC信号通路的活化,从而降低Hca-P细胞的淋巴道转移能力。
Objective: Hepatocyte growth factor is one kind of polypeptide cytokines generated from mesenchymal cells(such as mechanocyte and macrophage etc.). HGF has many important biological functions, such as promoting proliferation and division of cells; suppressing the formation of cell gap junctions and cell adhere lead to cell scattering ; up-regulating the expression of urokinase plasminogen activator and its receptor (uPA/uPAR), promoting the degradation of extracellular matrix; increasing the phosphorylation of cytoskeletal protein and interfering the rearrangment of cytoskeleton, which make cells apt to migration. So, HGF is also named as mitogenic factor、scattering factor and morphogen. HGF plays an important role in regulation of embryo development、organic formation、cells growth、proliferation and migration . It is also concerned with generation、development、diffusion and metastasis of tumor.
The receptor of HGF is coded by proto-oncogene c-met and is also called c-Met. c-Met is one member of receptor tyrosine protien kinase family and often expresses in epithelial cell(such as liver、kidney、enteron). The expression of c-Met in tumor cells is higher and has positive correlation with metastasis potential of tumor cell. HGF acts on target cell by paracrine after secretion from mesenchymal cells. Once conjugated with HGF, the receptors are dimerizated and activated, then ignite the signaling pathway in cells. It is known that, at least, there are three signaling pathways activated by HGF/c-Met, including MAPK signaling pathway, PLCγ1/DAG/PKC signaling pathway and PI3K/PKB signaling pathway. Among these, PI3K/PKB signaling pathway and PLCγ/PKC signaling pathway are the key pathways for regulating the invation and metastasis of tumor cell.
Both of KAI-1/CD82 and MRP-1/CD9 belong to the tetraspanin or trans- membrane-4 superfamily protens. CD82 is coded by tumor metastasis suppressor gene KAI-1. At present, It is konwed as a broad-spectrum suppressor of metastasis. CD9 is also called cell motility-related protein-1. Both of them can down-regulate the cell motility, and inhibit the invation and metastasis of tumor cell. A lot of experiment date has shown that CD82/CD9 can interact with c-Met, and thereby inhibits HGF-induced Met tyrosine kinase activity, as well as integrin to Met cross-talk, down-regulate PI3K/PKB and PLCγ/PKC signaling pathway. This is the mechanism by witch CD82 and CD9 down-regulate the cell motility, and inhibit the invation and metastasis of tumor cell.
Both of Hca-F cell strain and Hca-P cell strain are established from the same parental cell line. Hca-F is the high lymphatic metastasis potential cell strain and its lymphatic metastasis rate is 80%; Hca-P is low lymphatic metastasis potential cell strain and its lymphatic metastasis rate is 0-20%. However the molecular mechanism involved in the different lymphatic metastasis potential between these two cell strains remains unclear. To investigate the molecular mechanism of tumor lymphatic metastasis, The expression of CD8, CD9 and c-Met on Hca-F and Hca-P cells was examined and the activity of PI3K/PKB and PLCγ/PKC signaling pathway in two cell lines was analyzed comparatively.
Method: Hca-F cell and Hca-P cell were cultured in mouse abdominal cavities. Then the cells were harvested and the cytosol proteins and plasma membrane proteins were prepared. The expression of CD82/CD9 and activity of PI3K/PKB signaling pathway and PLCγ/PKC signaling pathway were analysed by using Western Blotting and computer scanning technique.
Result: 1)expression of CD82/CD9:The contents of CD9 have no significant difference between Hca-F cell and Hca-P cell, while the content of CD9 in Hca-P cell increased by 1.31 fold comparing with Hca-F cell, It suggests that CD9 maybe the key factor effecting the lymphatic metastasis potential of Hca-F and Hca-P cells.2) PI3K/ PKB signaling pathway: The distribution of PDK and the phosphorylation of PKB in Hca-F and Hca-P cell were analysed by using Western Blotting. The results shown that there were no significant differences on the expression of the phosphorylated PKB between the two cell lines; It is the same with the expression and distribution of PDK; The results suggest that PI3K/PKB signaling pathway isn’t the main pathway effecting the tumor lymphatic metastasis potential. 3) PLCγ1/PKC signaling pathway:The acti- vety of PLCγ1and different hypotypes of PKCs among these two cell strains were analyzed by using Western Blotting. The results displayed that phosphorylated PLCγ1 in Hca-P cell significantly decressed by 45.23% comparing with Hca-F cell. The contents of PKCα、PKCβ1and PKCβ2 were obviously decressed by 71.75%,76.80% and 73.16% comparing with Hca-F cell; The results showed that the activity of PLCγ1/PKC signaling pathway in Hca-F cell is higher than that of Hca-P cell. Thus, PLCγ1/PKC signaling pathway maybe the major pathway effecting the the tumor lym- phatic metastasis potential.
Conclusion:The expression of the tumor metastasis suppressor CD9 in Hca-P cell is higher comparing with Hca-F cell;Meantime, activity of PLCγ1/PKC signaling pathway in Hca-P cell has lower than that of Hca-F cell. These may be the important factors that effect the lymphatic metastasis potential of Hca-F and Hca-F cells.
HGF的受体(hepatocyte growth factor receptor, HGFR)是原癌基因c-met编码的产物,又称c-Met。c-Met属于受体酪氨酸蛋白激酶家族成员,常由上皮细胞(如肝、肾、消化道细胞)表达。c-Met在肿瘤细胞表达增加,并与肿瘤细胞转移能力呈正相关。HGF由间质细胞分泌后,经旁分泌途径作用于周围靶细胞。HGF与受体c-Met结合后,导致受体二聚化和活化,进而激活细胞内不同的信号转导途径。已知HGF/c-Met活化的细胞内信号转导途经起码有三条,包括有丝分裂原激活的蛋白激酶信号转导通路(MAPK信号通路)、磷脂酶Cγ1/二脂酰甘油/蛋白激酶C信号转导通路(PLCγ1 /DAG/PKC信号通路)和三磷脂酰肌醇激酶/蛋白激酶B信号转导通路(PI3K/ PKB信号通路)。其中,PI3K/PKB和PLCγ/PKC信号转导途径是调控肿瘤细胞侵袭和转移的重要途径。
KAI-1/CD82和MRP-1/CD9均属于4跨膜蛋白基因家族编码的产物。CD82是肿瘤转移抑制基因KAI-1编码的产物,目前被认为是广谱的肿瘤转移抑制因子。CD9又称细胞运动相关蛋白-1(motility-related protein-1)。二者均可下调癌细胞的运动性,从而抑制肿瘤细胞的浸润转移。对其作用机制研究表明,CD82和CD9通过与c-Met相互作用,抑制HGF诱导的c-Met酪氨酸蛋白激酶的活化,或抑制c-Met与整合素(integrins)的相互作用,下调c-Met对PI3K/PKB和PLCγ/PKC信号转导途径的活化,从而发挥其转移抑制作用。
Hca-F细胞株和HCa-P细胞株为同一来源但具有不同淋巴结转移能力的两个细胞株。Hca-F为高淋巴道转移株,淋巴结转移率为80%,Hca-P为低淋巴道转移株,淋巴结转移率为0-20%。两细胞株淋巴道转移能力差别产生的分子机制尚不十分清楚。本课题主要比较两细胞株CD82/CD9和c-Met的表达以及PI3K/PKB和PLCγ1 /PKC信号转导通路的活性变化,以探讨肿瘤细胞淋巴道转移的分子机制。
方法:小鼠腹水型肝癌Hca-F和Hca-P细胞株于小鼠腹腔培养。分别收集细胞后,分离提取细胞总蛋白,制备胞浆蛋白和颗粒结合蛋白。采用SDS-PAGE、Western Blotting技术及计算机扫描定量分析两细胞株CD82/CD9的表达和PI3K/PKB和PLCγ1 /PKC信号通路的活性。
结果:1)CD82/CD9的表达:CD82在高淋巴道转移株Hca-F细胞和低淋巴道转移株Hca-P细胞中的表达没有显著性差别,Hca-P细胞CD9表达显著高于Hca-F细胞(Hca-P是Hca-F的1.31倍,P=0.4%,n=3),提示CD9可能是影响两细胞株淋巴道转移能力的主要因素。2)PI3K/PKB信号转导通路:采用Western Blotting技术对两细胞株PDK的表达和在细胞中的分布以及PKB磷酸化活化进行了比较分析。结果显示,两细胞株磷酸化PKB的表达无显著性差别;PDK在两细胞株的分布也无显著差异;说明PI3K/PKB信号转导通路不是影响两细胞株淋巴道转移能力主要途径。3)PLCγ1/PKC信号转导通路:采用Western Blotting技术对两细胞株PLCγ1及不同亚型PKCs的活性进行了比较分析。结果显示,淋巴道低转移株Hca-P细胞磷酸化的PLCγ1表达明显低于淋巴道高转移株Hca-F细胞(Hca-P是Hca-F的45.23%倍,P<0.05,n=3);Hca-P细胞中膜结合的PKCα、PKCβ1和PKCβ2含量明显低于Hca-F细胞(Hca-P细胞PKCα、PKCβ1和PKCβ2分别是Hca-F细胞的71.75%、76.80%和73.16%,P<0.05,n=3)。说明高转移株Hca-F细胞的PLCγ1/PKC信号转导通路的活性高于低转移株Hca-P细胞。PLCγ1/PKC信号转导通路可能是影响两细胞株淋巴道转移能力主要信号途径。
结论:肿瘤转移抑制因子CD9在淋巴道低转移Hca-P细胞高表达;淋巴道低转移Hca-P细胞中的PLCγ1/PKC信号转导通路活性低。这可能是Hca-P细胞具有较低淋巴结转移能力的因素之一。推测可能是高表达的CD9与c-Met相互作用,抑制c-Met对Hca-P细胞PLCγ1/PKC信号通路的活化,从而降低Hca-P细胞的淋巴道转移能力。
Objective: Hepatocyte growth factor is one kind of polypeptide cytokines generated from mesenchymal cells(such as mechanocyte and macrophage etc.). HGF has many important biological functions, such as promoting proliferation and division of cells; suppressing the formation of cell gap junctions and cell adhere lead to cell scattering ; up-regulating the expression of urokinase plasminogen activator and its receptor (uPA/uPAR), promoting the degradation of extracellular matrix; increasing the phosphorylation of cytoskeletal protein and interfering the rearrangment of cytoskeleton, which make cells apt to migration. So, HGF is also named as mitogenic factor、scattering factor and morphogen. HGF plays an important role in regulation of embryo development、organic formation、cells growth、proliferation and migration . It is also concerned with generation、development、diffusion and metastasis of tumor.
The receptor of HGF is coded by proto-oncogene c-met and is also called c-Met. c-Met is one member of receptor tyrosine protien kinase family and often expresses in epithelial cell(such as liver、kidney、enteron). The expression of c-Met in tumor cells is higher and has positive correlation with metastasis potential of tumor cell. HGF acts on target cell by paracrine after secretion from mesenchymal cells. Once conjugated with HGF, the receptors are dimerizated and activated, then ignite the signaling pathway in cells. It is known that, at least, there are three signaling pathways activated by HGF/c-Met, including MAPK signaling pathway, PLCγ1/DAG/PKC signaling pathway and PI3K/PKB signaling pathway. Among these, PI3K/PKB signaling pathway and PLCγ/PKC signaling pathway are the key pathways for regulating the invation and metastasis of tumor cell.
Both of KAI-1/CD82 and MRP-1/CD9 belong to the tetraspanin or trans- membrane-4 superfamily protens. CD82 is coded by tumor metastasis suppressor gene KAI-1. At present, It is konwed as a broad-spectrum suppressor of metastasis. CD9 is also called cell motility-related protein-1. Both of them can down-regulate the cell motility, and inhibit the invation and metastasis of tumor cell. A lot of experiment date has shown that CD82/CD9 can interact with c-Met, and thereby inhibits HGF-induced Met tyrosine kinase activity, as well as integrin to Met cross-talk, down-regulate PI3K/PKB and PLCγ/PKC signaling pathway. This is the mechanism by witch CD82 and CD9 down-regulate the cell motility, and inhibit the invation and metastasis of tumor cell.
Both of Hca-F cell strain and Hca-P cell strain are established from the same parental cell line. Hca-F is the high lymphatic metastasis potential cell strain and its lymphatic metastasis rate is 80%; Hca-P is low lymphatic metastasis potential cell strain and its lymphatic metastasis rate is 0-20%. However the molecular mechanism involved in the different lymphatic metastasis potential between these two cell strains remains unclear. To investigate the molecular mechanism of tumor lymphatic metastasis, The expression of CD8, CD9 and c-Met on Hca-F and Hca-P cells was examined and the activity of PI3K/PKB and PLCγ/PKC signaling pathway in two cell lines was analyzed comparatively.
Method: Hca-F cell and Hca-P cell were cultured in mouse abdominal cavities. Then the cells were harvested and the cytosol proteins and plasma membrane proteins were prepared. The expression of CD82/CD9 and activity of PI3K/PKB signaling pathway and PLCγ/PKC signaling pathway were analysed by using Western Blotting and computer scanning technique.
Result: 1)expression of CD82/CD9:The contents of CD9 have no significant difference between Hca-F cell and Hca-P cell, while the content of CD9 in Hca-P cell increased by 1.31 fold comparing with Hca-F cell, It suggests that CD9 maybe the key factor effecting the lymphatic metastasis potential of Hca-F and Hca-P cells.2) PI3K/ PKB signaling pathway: The distribution of PDK and the phosphorylation of PKB in Hca-F and Hca-P cell were analysed by using Western Blotting. The results shown that there were no significant differences on the expression of the phosphorylated PKB between the two cell lines; It is the same with the expression and distribution of PDK; The results suggest that PI3K/PKB signaling pathway isn’t the main pathway effecting the tumor lymphatic metastasis potential. 3) PLCγ1/PKC signaling pathway:The acti- vety of PLCγ1and different hypotypes of PKCs among these two cell strains were analyzed by using Western Blotting. The results displayed that phosphorylated PLCγ1 in Hca-P cell significantly decressed by 45.23% comparing with Hca-F cell. The contents of PKCα、PKCβ1and PKCβ2 were obviously decressed by 71.75%,76.80% and 73.16% comparing with Hca-F cell; The results showed that the activity of PLCγ1/PKC signaling pathway in Hca-F cell is higher than that of Hca-P cell. Thus, PLCγ1/PKC signaling pathway maybe the major pathway effecting the the tumor lym- phatic metastasis potential.
Conclusion:The expression of the tumor metastasis suppressor CD9 in Hca-P cell is higher comparing with Hca-F cell;Meantime, activity of PLCγ1/PKC signaling pathway in Hca-P cell has lower than that of Hca-F cell. These may be the important factors that effect the lymphatic metastasis potential of Hca-F and Hca-F cells.
引文
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12. Cindy YF,Jeffery Jw,Kymberleey LS,et d1.Inhibition of integrin-linked kinase by a selective small molecule inhibitor,QLT0254,inhibits the PI3K/PKB/mTOR,STAT3 and FKHR path- ys and tumor growth,and enhances gemcitabine induced apoptosis in human orthotopie prima- ry pancreatic cancer xenografts[J].Cancer Res,2005,65(4):1497-1504.
13. Kim M S,Park M J,Moon E J,et a1.Hyaluronic acid induces osteopontin via the phospha- tidyIinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells[J].Cancer RPs,2005,65(3):686-691.
14. Zhong H,Chiles K,Feldser D,et a1.Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/Akt/FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics[J].Cancer Res,2000,60(6):1541-1545.
15. Bondar V M,Sweeney Gotsch B,Andreeff M,et a1.Inhibition of the phosphatidyhnositol 3-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo [J].Mol Cancer Ther,2002,l(12):989-997.
16. Tan J,Hallahan D E,et a1.Growth factor independent activation of protein kinase B contr- ibutes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response [J].Cancer Res.2003,63(22):7663-7667.
17. Adams JM,Cory S, at el.The bcl-2 family:arbiters of cell survival[J].Science,1998,281:1322-1326.
18.姜虹,吴焕明等,HGF/c-Met信号转导与肿瘤侵袭和转移的关系[J]。国外医学生理、病理学与临床分册,2003,3(23)532,632,732.
19. Borner C, Guadagno SN , Sh iao WWL , et al. Expression of four protein kinase C isoforms in rat fibroblasts[J]. J B io Chem , 1992, 267: 129.
19. Barsky SH, et al. Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis[J].Proc Natl Acod Sci USA.1988,85:612-616.
20. Dumont JA, Jones WD, Bilonti AJ, et al. Inhibition of experimental metastasis and cell adhesion of B16F3 melanoma cells by inhibitors of PKC[J].Cancer Research1992,52:1195- 1200.
21. Dumont JA, Jones WD, Bilonti AJ, et al. Inhibition of experimental metastasis and cell adhesion of B16F3 melanoma cells by inhibitors of PKC[J].Cancer Research1992,52:1195- 1200.
22. Jean M, et al. New clue to prostate cancer spread[J].Science,1995,268:799-800.
23. Dong JT, Lamb PW, Rinker-schaeffer CW, et al. KAI1,a metastasis suppressor gene for prost- ate cancer on human chromosome 11p11.2[J]. Science (Washington DC), 1995, 268:884-886.
24. Ono M, Handa K, Donald A, et al.Motility Inhibition and Apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9,with concurrent glycosyla- tion [J].Cancer Res,1999(59):2335-2339.
25. Liu WM, Zhang XA. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 2006 Aug 28;240(2):183-94.
26. Miyake M, Koyama M, Seno M, et al. Identification of the motility-related protein(MRP-1), recognized by monoclonal antibody M31-15,which inhibits cell motility[J].J Exp Med,1991,174(12):1347-1354
27. Miyake M, Nakano K, Ieki Y, et al. Motility related protein 1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer[J]. Cancer Res. 1995 Sep 15;55(18): 4127-31.
28. Uchida S,Shimada Y,Watanabe G, et al.Motility-related protein (MRP-1/CD9) and KAI1/ CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma[J]. Br J Cancer. 1999 Mar;79(7-8):1168-73.
29. Higashiyama M, Kodama K, Yokouchi H, Takami K, Adachi M, Taki T, Ishiguro S, Nakamori S, Yoshie O, Miyake M. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 1998 Aug 1;83(3): 466-74.
30. Takeda T, Hattori N, Tokuhara T, et al.Adenoviral transduction of MRP-1/CD9 and KAI1/ CD82 inhibits lymph node metastasis in orthotopic lung cancer model[J]. Cancer Res. 2007 Feb 15;67(4):1744-1749.
31. Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7.
32. Sridhar SC, Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin- dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 2006 Apr 13;25(16): 2367-78.
33. Takahashi M, Sugiura T, Abe M, Ishii K, Shirasuna K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer. 2007 Nov 1;121(9):1919-29
34. Todeschini AR, Dos Santos JN, et al. Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosy- napse[J]. J Biol Chem. 2007 Mar 16;282(11):8123-33.
35. Ono M, Handa K, et al. GM3 ganglioside inhibits CD9-facilitated haptotactic cell motility: coexpression of GM3 and CD9 is essential in the downregulation of tumor cell motility and malignancy[J]. Biochemistry. 2001 May 29;40(21):6414-6421.
36. Hakomori S. Carbohydrate-to-carbohydrate interaction, through glycosynapse, as a basis of cell recognition and membrane organization. Glycoconj J. 2004;21(3-4):125-37.
37. Regina Todeschini A, Hakomori SI. Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta. 2008 Mar;1780(3):421-33.
38. Kojima N, Hakomori S. Cell adhesion, spreading, and motility of GM3-expressing cells basedon glycolipid-glycolipid interaction. J Biol Chem. 1991 Sep 15;266(26):17552-8.
39. Mitsuzuka K, Handa K, et al. A specific microdomain ("glycosynapse 3") controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of alpha3beta1 integrin with CD9[J]. J Biol Chem. 2005 Oct 21;280(42):35545-53.
40. Kawakami Y, Kawakami K, et al. Tetraspanin CD9 is a "proteolipid," and its interaction with alpha 3 integrin in microdomain is promoted by GM3 ganglioside, leading to inhibition of laminin-5-dependent cell motility[J]. J Biol Chem. 2002 Sep 13;277(37):34349-58.
41. Todeschini AR, Dos Santos JN, Handa K, Hakomori SI. Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1925-30.
42. Toledo MS, Suzuki E, Handa K, Hakomori S. Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J Biol Chem. 2005 Apr 22;280(16):16227-34.
43. Iwabuchi K, Yamamura S, Prinetti A, Handa K, Hakomori S. GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. J Biol Chem. 1998 Apr 10;273(15):9130-8.
1. Jiang WG,Marlin TA,Parrc,et a1.Hepatoeyte growth factor,its receptor,and their potential value in cancer therapies[J].Hematology,2005,53:35-61.
2. C. BAYKAL, E. DEMIRTAS, A. AL, A. AYHAN, K. YUCE, et al. Comparison of HGF (hepatocyte growth factor) levels of epithelial ovarian cancer cyst fluids with benign ovarian cysts[J]. Int J Gynecol Cancer, 2003, 13:771-775.
3. G Shiota, DB Rhoads, TC Wang, T Nakamura, and EV Schmidt. Hepatocyte Growth Factor Inhibits Growth of Hepatocellular Carcinoma Cells[J]. Proc. Nati. Acad. Sci. USA, 1992, 89: 373-377.
4. Naldini L, Vigna E, Narsimhan RP, et al. Hepatocyte growth factor(HGF) stimulates the tyrosine activity of the receptor encoded by the proto-oncogene c-Met[J]. Oncogene,1991,6(4): 501-504
5. Ivan M,Bond JA,Prat M,et a1.Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells. [J].Oncogene,1997,14:2417-2423.
6. webb CP,Taylor GA,Jeffers M,et a1.Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. [J].Oncogene,l998,17:2019-2025.
7. Jean M, et al. New clue to prostate cancer spread[J].Science,1995,268:799-800.
8. Liu WM, Zhang XA. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 2006 Aug 28;240(2):183-94.
9. Miyake M, Koyama M, Seno M, et al. Identification of the motility-related protein(MRP-1),recognized by monoclonal antibody M31-15,which inhibits cell motility[J].J Exp Med,1991,174(12):1347-1354.
10. Miyake M, Nakano K, Ieki Y, et al. Motility related protein 1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer[J]. Cancer Res. 1995 ,Sep 15;55 (18): 4127-31.
11. Uchida S, Shimada Y, Watanabe G, et al.Motility-related protein (MRP-1/CD9) and KAI1/CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma[J]. Br J Cancer. 1999 Mar;79(7-8):1168-73.
12. Higashiyama M, Kodama K, Yokouchi H, Takami K, Adachi M, Taki T, Ishiguro S, Nakamori S, Yoshie O, Miyake M. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 1998 Aug 1;83(3): 466-74.
13. Takeda T, Hattori N, Tokuhara T, et al.Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model[J]. Cancer Res. 2007 Feb 15;67(4):1744-1749.
14. Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7.
15. Sridhar SC, Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin- dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 2006 Apr 13;25(16): 2367-78.
16. Takahashi M, Sugiura T, Abe M, Ishii K, Shirasuna K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer. 2007 Nov 1;121(9): 1919-29
17. Todeschini AR, Dos Santos JN, et al. Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosynapse[J]. J Biol Chem. 2007 Mar 16;282(11):8123-33.
18. Kawakami Y, Kawakami K, et al. Tetraspanin CD9 is a "proteolipid," and its interaction with alpha 3 integrin in microdomain is promoted by GM3 ganglioside, leading to inhibition of laminin-5-dependent cell motility[J]. J Biol Chem. 2002 Sep 13;277(37):34349-58.
19. Toledo MS, Suzuki E, Handa K, Hakomori S. Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J Biol Chem. 2005 Apr 22;280(16):16227-34.
20.马克里,朱正美等,具不同淋巴道转移潜能小鼠肝癌瘤株细胞膜鞘糖脂比较研究[J]。生物化学杂志。1996,3(12):360-363
2. Yama guchi R, Yano H, Lemura A, et al.Expression of vascular endothelial growth factor in hu- man hepatocell ularcinoma[J].Hepatology,1998,28(1):68-77.
3. Matsumoto K,Nakamura T,Kramer RH,et a1. Hepatocyte growth factor/scatter factor in- duces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. [J].Biol Chem,l994,269(50):3l807- 3l8l3.
4. Dong G,Chen Z,Li ZY,et a1.Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleuk- in-8 and vascular endothelial growth factor in head and neck squaruous cell catcinoma [J].Can- cer Res,2001,61:5911-5918.
5.汪进国,耿小平等。HGF/cMet信号转导对肝细胞肝癌的侵袭和转移的作用[J]。临床肝胆病杂志,2002,18(3):731-732.
6. Nakanishi K, Fujimoto I,Ueki T, et al.Hepatocyte growth factor promotes migration of human hepatocell ularcarcinoma via phosphatidylinosital3-kinase[J].Clin Exp Metastasis,1999,17(6):507-514.
7. Lee HS, Huang AM, Huang GT,et al.Hepaticyte growth factor stimulate the growth and active- tes mitogen-activated protein kinase in human heptomacells[J].JBiomed Sci,1998,5(3):180-184.
8. Recio JA, Merlino G, et al.Hepatocyte growth factor/scatter factor activates proliferation in me- lanomacells through p38 MAPK,ATF-2 and cyclinD1[J].Oncogene,2002,21(7):1000-1008.
9. Hili K,Weiti S,Yu J,et a1.Specific requirement for the p85 pl10 alpha phosphatidylinositol 3-kinase during epidermal growth factor-stimulated actin nucleation in breast cancer cells [J].J- ol Chem,2000,275(6):3741-3744.
10. Maier D,Jones G,Li X,et a1.The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells[J].Cancer Res,1999,59(21):5479-5482.
11. Gambalettad D,Marchetti A,Benedetti I.et a1.Cooperative signaling between alpha(6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinas dependent inv- n[J].J Bibl Chem,2000,275(14):10604-10610.
12. Cindy YF,Jeffery Jw,Kymberleey LS,et d1.Inhibition of integrin-linked kinase by a selective small molecule inhibitor,QLT0254,inhibits the PI3K/PKB/mTOR,STAT3 and FKHR path- ys and tumor growth,and enhances gemcitabine induced apoptosis in human orthotopie prima- ry pancreatic cancer xenografts[J].Cancer Res,2005,65(4):1497-1504.
13. Kim M S,Park M J,Moon E J,et a1.Hyaluronic acid induces osteopontin via the phospha- tidyIinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells[J].Cancer RPs,2005,65(3):686-691.
14. Zhong H,Chiles K,Feldser D,et a1.Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/Akt/FRAP pathway in human prostate cancer cells:implications for tumor angiogenesis and therapeutics[J].Cancer Res,2000,60(6):1541-1545.
15. Bondar V M,Sweeney Gotsch B,Andreeff M,et a1.Inhibition of the phosphatidyhnositol 3-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo [J].Mol Cancer Ther,2002,l(12):989-997.
16. Tan J,Hallahan D E,et a1.Growth factor independent activation of protein kinase B contr- ibutes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response [J].Cancer Res.2003,63(22):7663-7667.
17. Adams JM,Cory S, at el.The bcl-2 family:arbiters of cell survival[J].Science,1998,281:1322-1326.
18.姜虹,吴焕明等,HGF/c-Met信号转导与肿瘤侵袭和转移的关系[J]。国外医学生理、病理学与临床分册,2003,3(23)532,632,732.
19. Borner C, Guadagno SN , Sh iao WWL , et al. Expression of four protein kinase C isoforms in rat fibroblasts[J]. J B io Chem , 1992, 267: 129.
19. Barsky SH, et al. Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis[J].Proc Natl Acod Sci USA.1988,85:612-616.
20. Dumont JA, Jones WD, Bilonti AJ, et al. Inhibition of experimental metastasis and cell adhesion of B16F3 melanoma cells by inhibitors of PKC[J].Cancer Research1992,52:1195- 1200.
21. Dumont JA, Jones WD, Bilonti AJ, et al. Inhibition of experimental metastasis and cell adhesion of B16F3 melanoma cells by inhibitors of PKC[J].Cancer Research1992,52:1195- 1200.
22. Jean M, et al. New clue to prostate cancer spread[J].Science,1995,268:799-800.
23. Dong JT, Lamb PW, Rinker-schaeffer CW, et al. KAI1,a metastasis suppressor gene for prost- ate cancer on human chromosome 11p11.2[J]. Science (Washington DC), 1995, 268:884-886.
24. Ono M, Handa K, Donald A, et al.Motility Inhibition and Apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9,with concurrent glycosyla- tion [J].Cancer Res,1999(59):2335-2339.
25. Liu WM, Zhang XA. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 2006 Aug 28;240(2):183-94.
26. Miyake M, Koyama M, Seno M, et al. Identification of the motility-related protein(MRP-1), recognized by monoclonal antibody M31-15,which inhibits cell motility[J].J Exp Med,1991,174(12):1347-1354
27. Miyake M, Nakano K, Ieki Y, et al. Motility related protein 1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer[J]. Cancer Res. 1995 Sep 15;55(18): 4127-31.
28. Uchida S,Shimada Y,Watanabe G, et al.Motility-related protein (MRP-1/CD9) and KAI1/ CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma[J]. Br J Cancer. 1999 Mar;79(7-8):1168-73.
29. Higashiyama M, Kodama K, Yokouchi H, Takami K, Adachi M, Taki T, Ishiguro S, Nakamori S, Yoshie O, Miyake M. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 1998 Aug 1;83(3): 466-74.
30. Takeda T, Hattori N, Tokuhara T, et al.Adenoviral transduction of MRP-1/CD9 and KAI1/ CD82 inhibits lymph node metastasis in orthotopic lung cancer model[J]. Cancer Res. 2007 Feb 15;67(4):1744-1749.
31. Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7.
32. Sridhar SC, Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin- dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 2006 Apr 13;25(16): 2367-78.
33. Takahashi M, Sugiura T, Abe M, Ishii K, Shirasuna K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer. 2007 Nov 1;121(9):1919-29
34. Todeschini AR, Dos Santos JN, et al. Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosy- napse[J]. J Biol Chem. 2007 Mar 16;282(11):8123-33.
35. Ono M, Handa K, et al. GM3 ganglioside inhibits CD9-facilitated haptotactic cell motility: coexpression of GM3 and CD9 is essential in the downregulation of tumor cell motility and malignancy[J]. Biochemistry. 2001 May 29;40(21):6414-6421.
36. Hakomori S. Carbohydrate-to-carbohydrate interaction, through glycosynapse, as a basis of cell recognition and membrane organization. Glycoconj J. 2004;21(3-4):125-37.
37. Regina Todeschini A, Hakomori SI. Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta. 2008 Mar;1780(3):421-33.
38. Kojima N, Hakomori S. Cell adhesion, spreading, and motility of GM3-expressing cells basedon glycolipid-glycolipid interaction. J Biol Chem. 1991 Sep 15;266(26):17552-8.
39. Mitsuzuka K, Handa K, et al. A specific microdomain ("glycosynapse 3") controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of alpha3beta1 integrin with CD9[J]. J Biol Chem. 2005 Oct 21;280(42):35545-53.
40. Kawakami Y, Kawakami K, et al. Tetraspanin CD9 is a "proteolipid," and its interaction with alpha 3 integrin in microdomain is promoted by GM3 ganglioside, leading to inhibition of laminin-5-dependent cell motility[J]. J Biol Chem. 2002 Sep 13;277(37):34349-58.
41. Todeschini AR, Dos Santos JN, Handa K, Hakomori SI. Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1925-30.
42. Toledo MS, Suzuki E, Handa K, Hakomori S. Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J Biol Chem. 2005 Apr 22;280(16):16227-34.
43. Iwabuchi K, Yamamura S, Prinetti A, Handa K, Hakomori S. GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. J Biol Chem. 1998 Apr 10;273(15):9130-8.
1. Jiang WG,Marlin TA,Parrc,et a1.Hepatoeyte growth factor,its receptor,and their potential value in cancer therapies[J].Hematology,2005,53:35-61.
2. C. BAYKAL, E. DEMIRTAS, A. AL, A. AYHAN, K. YUCE, et al. Comparison of HGF (hepatocyte growth factor) levels of epithelial ovarian cancer cyst fluids with benign ovarian cysts[J]. Int J Gynecol Cancer, 2003, 13:771-775.
3. G Shiota, DB Rhoads, TC Wang, T Nakamura, and EV Schmidt. Hepatocyte Growth Factor Inhibits Growth of Hepatocellular Carcinoma Cells[J]. Proc. Nati. Acad. Sci. USA, 1992, 89: 373-377.
4. Naldini L, Vigna E, Narsimhan RP, et al. Hepatocyte growth factor(HGF) stimulates the tyrosine activity of the receptor encoded by the proto-oncogene c-Met[J]. Oncogene,1991,6(4): 501-504
5. Ivan M,Bond JA,Prat M,et a1.Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells. [J].Oncogene,1997,14:2417-2423.
6. webb CP,Taylor GA,Jeffers M,et a1.Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. [J].Oncogene,l998,17:2019-2025.
7. Jean M, et al. New clue to prostate cancer spread[J].Science,1995,268:799-800.
8. Liu WM, Zhang XA. KAI1/CD82, a tumor metastasis suppressor. Cancer Lett. 2006 Aug 28;240(2):183-94.
9. Miyake M, Koyama M, Seno M, et al. Identification of the motility-related protein(MRP-1),recognized by monoclonal antibody M31-15,which inhibits cell motility[J].J Exp Med,1991,174(12):1347-1354.
10. Miyake M, Nakano K, Ieki Y, et al. Motility related protein 1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer[J]. Cancer Res. 1995 ,Sep 15;55 (18): 4127-31.
11. Uchida S, Shimada Y, Watanabe G, et al.Motility-related protein (MRP-1/CD9) and KAI1/CD82 expression inversely correlate with lymph node metastasis in oesophageal squamous cell carcinoma[J]. Br J Cancer. 1999 Mar;79(7-8):1168-73.
12. Higashiyama M, Kodama K, Yokouchi H, Takami K, Adachi M, Taki T, Ishiguro S, Nakamori S, Yoshie O, Miyake M. KAI1/CD82 expression in nonsmall cell lung carcinoma is a novel, favorable prognostic factor: an immunohistochemical analysis. Cancer. 1998 Aug 1;83(3): 466-74.
13. Takeda T, Hattori N, Tokuhara T, et al.Adenoviral transduction of MRP-1/CD9 and KAI1/CD82 inhibits lymph node metastasis in orthotopic lung cancer model[J]. Cancer Res. 2007 Feb 15;67(4):1744-1749.
14. Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7.
15. Sridhar SC, Miranti CK. Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin- dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 2006 Apr 13;25(16): 2367-78.
16. Takahashi M, Sugiura T, Abe M, Ishii K, Shirasuna K. Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer. 2007 Nov 1;121(9): 1919-29
17. Todeschini AR, Dos Santos JN, et al. Ganglioside GM2-tetraspanin CD82 complex inhibits met and its cross-talk with integrins, providing a basis for control of cell motility through glycosynapse[J]. J Biol Chem. 2007 Mar 16;282(11):8123-33.
18. Kawakami Y, Kawakami K, et al. Tetraspanin CD9 is a "proteolipid," and its interaction with alpha 3 integrin in microdomain is promoted by GM3 ganglioside, leading to inhibition of laminin-5-dependent cell motility[J]. J Biol Chem. 2002 Sep 13;277(37):34349-58.
19. Toledo MS, Suzuki E, Handa K, Hakomori S. Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J Biol Chem. 2005 Apr 22;280(16):16227-34.
20.马克里,朱正美等,具不同淋巴道转移潜能小鼠肝癌瘤株细胞膜鞘糖脂比较研究[J]。生物化学杂志。1996,3(12):360-363